Targeting AKT Activation in Relapsed CLL Disease Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the USA and is currently an incurable disease. Despite the high response rate to initial chemoimmunotherapies, most treated CLL patients will relapse and eventually die of the disease. Bendamustine (an alkylating agent) and Rituximab (an antibody targeting CD20) combination therapies have emerged as one of the effective approaches used in the relapsed CLL; however, only ~15% complete remission can be achieved. Most patients responding to second line therapies only have short-term treatment free survival and experience a quick relapse. Therefore, safe and effective therapies are greatly needed for this cohort of CLL patients. A primary reason for resistance is that CLL leukemic cells have intimate contact with their microenvironment components and this interaction is critical for maintaining their survival and mediates drug resistance. There is now significant and growing data supporting the key role of phosphoinositide 3- kinase (PI3K)/Akt signals in promoting leukemic cell survival and proliferation. Our data indicates that platelet derived growth factor (PDGF) secreted by CLL B-cells modulates stromal cell proliferation and subsequent vascular endothelial growth factor (VEGF) production in marrow stromal cells (MSC) through a PI3K/Akt signal activation pathway. We believe that PI3K/Akt is critical for CLL-stroma interaction and events related to disease progression and drug resistance. MK2206, an oral allosteric potent Akt inhibitor, has been tested for its safety in a phase I trial of refractory solid tumor. Our preclinical investigation demonstrated that Akt inhibition with MK2206 synergizes with Bendamustine to promote CLL apoptosis in vitro. In this proposal, we will investigate if targeting Akt activation will result in robust promotion of CLL apoptosis by altering signal activation in both leukemic cells and marrow stroma cells and will increase clinical efficacy of standard CLL therapies. To achieve these goals, we will conduct a phase I/II clinical trial to test the novel combination therapies of Akt inhibition with MK2206 with Bendamustine and Rituximab in relapsed CLL patients. We also plan to study the functional impact of Akt inhibition on CLL signal activation, survival and sensitivity to standard CLL agents. Finally, we will test the functional impact of Akt inhibition on stromal cell functions as we believe that targeting Akt will disrupt stroma-mediated apoptosis resistance of CLL. Collectively, these studies are designed to develop a strategy to combine PI3K/Akt inhibition with novel targeted approaches to enhance current therapies for relapsed CLL patients. These studies will be conducted within the context of a career development plan aimed at preparing the principle investigator for an independent career as a clinical investigator. Dr. Wei Ding, the principle investigator of the research proposal, has a solid biomedical research background from her Ph.D. training and recent investigation on the CLL microenvironment. Her immediate career goal is to gain experience in clinical trial design, regulation and completion of the correlative studies. This goal will be achieved by performing her first clinical trial and correlative studies, working closely with established mentors, and taking courses from Clinical and Translational Sciences at Mayo Graduate School. The long-term career goal of Dr. Ding is to become an independent clinical investigator capable of translating biologic insights to the clinic by developing novel targeted approach to augment current CLL therapies. The Mayo Clinic Hematology program provides support for Dr. Ding with extensive resources for clinical and translational research development. These resources include a well organized clinical trial unit, a large patient volume, outstanding clinical and research database, excellent translational scientists as collaborators and ample research space. Drs. Neil Kay and .Scott Kaufmann serve as Dr. Ding's mentor and co-mentor. Both have a track record of developing junior faculties to independent investigators. With the assistance of this K23 award, Dr. Ding will be in a unique position to capitalize on the educational, patient, and scientific resources available to her at Mayo Clinic to make a significant impact on the biology and therapy of CLL.